CDK9 inhibitors reactivate p53 by downregulating iASPP

摘要: Loss of p53's tumor-suppressive function, either via TP53 mutation or hyperactive p53 inhibitory proteins, is one the most frequent events in development human cancer. Here, we describe a strategy pharmacologically inhibiting iASPP, negative regulator p53, to restore wild-type function. iASPP knockdown colon cancer cell line HCT116 efficiently promoted transcriptional activity and induced p53-dependent death, suggesting key role for silencing this line. Screening preclinical clinical drug library using isogenic models revealed that cyclin-dependent kinase 9 (CDK9) inhibitors preferentially inhibit p53+/+, rather than p53-/-, cells. Mechanistically, CDK9 downregulated at level. This downregulation was dose- time-dependent. further showed synergistic effects killing p53+/+ cells when combined with MDM2 inhibitor Nutlin-3. In large TCGA pan-cancer cohort, overexpression predicted poor overall survival (OS) patients, worse OS observed simultaneously overexpressed. Our study identifies as p53-reactivating agents, proposes treat by reactivating concurrent inhibition MDM2.